The present invention relates to a method for modulating the activity of one or more enzymes that produce precursors of lipid metabolites associated with gastric inflammation, to reduce the deleterious effects of gastric inflammation and to enhance animal and human growth or improve feeding efficiency.
Enhancing animal growth or feed efficiency, can have substantial impact on, for example, the animal meat industry by reducing the high cost of feeding food-producing animals and directly improving profitability. For example, in the poultry industry, even a slight increase in broiler growth rate coupled with reduced feed consumption brings the broiler to market maturity faster at lower cost. With approximately seven billion broilers raised annually in the United States, significant savings are realized.
Methods are known for controlling feeding behavior by modulating the activity of gut peptides that control gastrointestinal motility. These gut peptides include cholecystokinin (CCK), the avian pancreatic polypeptide (aPP), bombesin, gastrin, somatostatin, and neuropeptide Y. Duke, G. E., "Recent Studies on Regulation of Gastric Motility in Turkeys," World's Poultry Science Association Invited Lecture, pp. 1-8 (1991); Baile et al., "Hormones and feed intake," Proc. Nutr. Soc., 42:113-27 (1983). The effect upon feeding behavior of physiological regulators other than the gut peptides is largely unknown.
One set of such regulators include inflammatory metabolites such as the leukotrienes and the prostaglandins which can have beneficial, as well as damaging, effects on the host.
In animals, linoleic acid is converted to arachidonic acid. Arachidonic acid is released (as arachidonate) from the sin 2 position of membrane phospholipids by phospholipase A.sub.2 (PLA.sub.2) and is converted by lipoxygenase or cyclooxygenase into precursors for biologically active prostaglandins and leukotrienes. Perhaps as a result of artificially high dietary linoleic acid levels, animals can contain high levels of the prostaglandin and leukotriene precursors.
Prostaglandins are C.sub.20 fatty acids formed from arachidonic acid by cyclooxygenase activity. Prostaglandins cause inflammatory effects during gastrointestinal traumas, such as colitis and ulcers, and are involved in vasodilation, vasoconstriction, and stimulation of intestinal or bronchial smooth muscle. Prostaglandins are found in inflammatory exudates and can induce fever and erythema. Leukotrienes, which are formed from arachidonic acid in response to immunological or non-immunological leucocytes and macrophages stimulation, cause contraction of smooth muscle, such as intestinal smooth muscle, attract leukocytes and stimulate vascular permeability.
It may be possible to reduce inflammation by reducing gastrointestinal prostaglandin synthesis, perhaps by using selective inhibitors of cyclooxygenase-2, an enzyme expressed at inflammation sites. This would reduce or eliminate the need for standard nonsteroidal anti-inflammatory drugs which are known to have ulcerogenic side effects. However, Reuter et al. have shown that inhibition of cyclooxygenase products, such as prostaglandin, exacerbated colitis and increased inflammation-associated colonic injury. Reuter et al., "Exacerbation of Inflammation-associated Colonic Injury in Rat through Inhibition of Cyclooxygenase-2," J. Clin. Invest., 98(9):2976-85 (1996). Likewise, Uribe et al. have shown that using indomethacin to inhibit prostaglandin synthesis causes intestinal ulcers. Uribe et al., "Endogenous Prostaglandins and Microflora Modulate DNA Synthesis and Neuroendocrine Peptides in the Rat Gastrointestinal Tract," Scand. J. Gastro., 32:691-99 (1997). Other research has shown that prostaglandins are necessary for gut function repair. Blikslager et al., "Prostaglandins I.sub.2 and E.sub.2 Have a Synergistic Role in Rescuing Epithelial Barrier Function in Porcine Ileum," J. Clin. Invest., 100(8): 1928-33 (1997).
These findings suggest that downregulating prostaglandin activity would be deleterious to an animal's gastrointestinal system.